Abstract: Vanadium is a ductile and malleable transition metal and has a wide application in a range of industries such as automotive, aerospace, chemistry and agriculture industries. A great amount of the environmental vanadium comes from human activity, particularly burning of crude oil and coal, as well as metallurgic and mining activities. The major risk for human exposure to vanadium is through inhalation of particulate matter (PM) generated by fuel combustion. Occupational exposure to vanadium pentoxide (V2O5) in humans were reported to link to asthma and chronic bronchitis. Furthermore, increased vanadium concentration in ambient PM2.5 was found to associate with asthma and asthma exacerbation in young children. The prominent features of asthma and chronic bronchitis include inflammation and mucus hypersecretion. We reported that respiratory exposure to V2O5 caused inflammation and airway mucous cell metaplasia (MCM), a significant increase of mucous cell number causing mucus hypersecretion, in a mouse model of Vanadium Induced Pulmonary Toxicity (VIPT), supporting the observational finding from human exposure. In the present study, we have identified a quantitative trait locus on mouse chromosome 11 containing Ppp3r1, a regulatory component of calcineurin (CN), which was significantly associated with vanadium induced MCM. We further demonstrate that CN inhibition by Cyclosporine A rendered the susceptible A/J mice resistant to VIPT. Thus, we plan to test a novel hypothesis that CN may be an important determinant of the susceptibility to VIPT that particularly affects airway epithelium, a critical barrier and innate immune regulator in almost all lung illnesses. Thus, we propose to first determine the mechanistic role of CN in mediating susceptibility to VIPT using both gain-of-function CN model and CN inhibition model (Aim1). We will also extend our preliminary study that was performed mainly in a high-dose acute V2O5 model to a novel long-term inhalational model that is close to real-life environmental vanadium exposure. We will determine the role of CN in mediating long-term VIPT (Aim2). Successful completion of this proposal will advance our understanding of how vanadium interacts with pulmonary system and elicits toxicity. Additionally, it will be also highly translatable as our novel findings and novel models will inform new therapeutic target for the chronic lung diseases characterized by mucous hypersecretion such as asthma, chronic bronchitis etc. which are also the major illnesses caused by vanadium exposure.